Introduction 

Eosinophilic gastrointestinal diseases (EGID) are rare inflammatory disorders, characterised by eosinophilic infiltration in parts of the gastrointestinal tract without any other known causes of the inflammation.¹ Eosinophils are a type of white blood cell which support the immune system and are very important when it comes to defending the body against allergens. Eosinophilia occurs when you have more eosinophils in your blood than normal which leads to inflammation and swelling. This eosinophilia is found in eosinophilic gastrointestinal diseases.

There are four main types of EGID: Eosinophilic Oesophagitis (EoE), Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN) and Eosinophilic Colitis (EoC).² While EoE in children is a well-defined disease with established guidelines, the other three EGID are extremely rare and have a limited evidence base.³ 

This article takes a deep dive into these rare gastrointestinal disorders in children and addresses signs, risk factors, diagnosis and treatment options. 

What are eosinophilic gastrointestinal diseases

EGID is a rare heterogeneous disease group. This means there are a wide range of causes, symptoms and severity levels. The disease will selectively affect one or more parts of the gastrointestinal tract with eosinophilic inflammation.

It is now widely recognised that chronic allergic reactions, primarily caused by food allergens, play a crucial role in the development of EGID.⁴ Different types of EGID have varied histopathologic features, which are those features affecting the tissues or cells of the gastrointestinal tract. They also have varied eosinophil density, which is the amount of eosinophils clumped together in the affected tissue.

Eosinophilic eosophagitis (EoE)

EoE is the most common EGID with an estimated prevalence of 1 in 2000.⁵ EoE impacts the function of the oesophageal epithelium - these are the cells that line the protective mucosal layer of the oesophagus. The combined effect of food allergens, disruptions in the oesophagus’s epithelium, and possible shifts in its microbial community can allow allergens to penetrate the protective layer.⁴ This interaction triggers the immune system and also dysregulates key genes involved in epithelial barrier function. This can lead to changes in the structure of the oesophagus which impacts swallowing over time.

Eosinophilic gastritis (EoG) and Eosinophilic Enteritis (EoN)

EoG and EoN are more rare with an estimated prevalence of 2 to 5 per 100,000.⁶ EoG is defined by the presence of eosinophilic inflammation in the stomach which can also spread to the oesophagus. EoN involves the small interesting - the duodenum and ileum. However, EoN can occur concomitantly with EoG. Exposure to food triggers and stimulates the development of an immune response which leads to inflammation in these areas. EoG and EoN are strongly linked to allergic disorders.⁶

Eosinophilic colitis (EoC)

EoC is the most rare of the EGID with an estimated prevalence of just 3 per 100,000.⁶ The underlying mechanism of EoC involves abnormal hypersensitivity and often an association with food allergens. There is an infiltration of eosinophils into the colon, accompanied by increased levels of IgE (antibodies involved in allergic responses) and IL-5 (cytokines involved in the growth and activity of eosinophils) in the bloodstream.

Common signs and symptoms

In children, EGID usually presents with various gastrointestinal symptoms. These depend on the affected segment and the extent of eosinophilic inflammation.³

EoE may cause symptoms like vomiting, abdominal pain, and feeding difficulties. As children get older, the presentation tends to shift more towards dysphagia (which is difficulty swallowing) and food impaction. These symptoms are more common in adolescents and adults. 

For the other three types of EGID, symptoms can vary depending on how deeply the eosinophilic infiltration is into the the intestinal wall.⁷ There are three categories:

1. Musosal: children tend to have non-specific symptoms, such as nausea, vomiting, diarrhoea and anaemia. Weight loss and protein losing enteropathy are the most common manifestations
2. Muscular: the involvement of this layer leads to intestinal obstruction which happens after the thickening of the intestinal wall. Symptoms can include pain, vomiting and ascites
3. Serosal: this subtype usually begins with ascites and can be associated with symptoms of intestinal obstruction like cramping, loss of appetite, vomiting and constipation

Causes and risk factors

Gastrointestinal eosinophilic inflammation is associated with seasonal allergies, food allergies, asthma, eczema, and atopy.⁸ Atopic diseases include asthma, allergies and eczema occurring together. 

The eosinophil-mediated immune responses that lead to the development of EGID are related to the production of IgE antibodies to foods that are being eaten. This is when the immune system reacts abnormally to a food - for example wheat or dairy. This abnormal reaction can lead to an activation of Th2 immune cells. These immune cells are vital for the immune system but over-activation can lead to chronic allergic diseases like asthma and allergies. This over-activation leads to increased inflammation which causes an excessive tissue eosinophil load in the tissues of the gastrointestinal tract.

Multiple research studies have reported a strong familial component to EoE involving approximately 13 genes.⁹ Studies have also looked at the early life environment which includes the amount of antibiotics used in mother or infant, proton pump inhibitor usage, and home pet exposure. These are also thought to play a key role in disease development. At the moment, there are no studies looking at genetic risk factors and interplay with the environment for the other EGID although one would expect there to be a similar correlation.

Similar to what is being discovered in other gastrointestinal disorders, there is increasing evidence that the gut microbiome has a role in EGIDs. These are the microorganisms that live in your gut and directly impact your health in different ways. Research shows that there are specific changes in the microbiome of those with active disease.¹⁰ 

Diagnosis

In practice, it is difficult to detect and diagnose EGID in children since a formal diagnosis requires an endoscopy, which is an invasive test. Other test findings which are not conclusive include a high level of eosinophils in the blood (which does not occur in all children) as well as increased faecal calprotectin, which is a marker of gastrointestinal inflammation. If a child does have high levels of fecal calprotectin, further evaluation with endoscopy is usually advised.³

Tissue samples taken during an endoscopy will allow for histological confirmation of tissue eosinophilia. This will depend on the location of the EGID, and the amount of eosinophils in a specimen when viewed under a microscope - known as high power field (HPF):

• Eosinophilic oesophagitis: ≥ 15 HPF (≥ - is defined as greater than or equal to)
• Eosinophilic gastritis: ≥ 20-30 HPF
• Eosinophilic enteritis ≥ 20 HPF
• Eosinophilic colitis: ≥ 25-50 HPF

Treatment options and management

Apart from EoE, there are no universally accepted treatment strategies for EGID. At this stage, international consensus and clinical guidelines are lacking. In practice, the treatment of EGID will be individualised for your child and determined according to symptoms and response time.⁷

Diet therapy

As EGID is related to food allergy, dietary modifications are a common strategy. These usually involve one of the following:

• Targeted elimination diet - results from food allergy tests such as a specific IgE or a skin prick test, will determine which foods are removed
• 6-food elimination diet - this includes the restriction of six foods which are milk, soy, egg, wheat, nuts, and seafood
• Elemental diet - this is a liquid meal replacement which comprises proteins, carbohydrates and fats in their most elemental (or broken-down) form

Pharmacologic therapy

Pharmacologic strategies for EGID in children are controversial as there are insufficient research studies.³ However, the following medications can be used depending on the child and presenting symptoms:

• Proton pump inhibitors, which suppress acid in the stomach and may thereby reduce mucosal inflammation leading to a reduction in tissue eosinophils
• Selective leukotriene-4 receptor antagonist, like montelukast, which can lead to remission in EoG and EoN
• Mast cell stabilizers, like sodium cromolyn, which can prevent allergic responses; however, their efficacy is controversial
• Systemic steroids, like prednisone, can lead to remission but do not usually maintain remission
• Other experimental drugs include:
  • Immunosupressants (azathioprine, 6-mercaptopurine)
  • Anti-tumor necrosis factor monoclonal antibody (infliximab, adalimumab) 
  • Anti-IgE antibody (omalizumab)
  • Anti-IL-5 antibody (mepolizumab)
  • Th2 inhibitors (suplatast) 

Long-term outlook

Apart from EoE, no studies have examined the long-term outlook of EGID.³ 

In EoE, the majority of cases in children may persist throughout adulthood. Research shows that relapse is present in 32.5% to 49.2% of cases.¹¹ Getting an early diagnosis is essential as the high risk of oesophageal stricture increases about 9% annually in those untreated. 

To ensure better clinical outcomes, it is important to diagnose and treat EGID properly as early as possible, especially in children. It is unlikely that symptoms will improve without treatment and this will lead to malabsorption, malnutrition, and growth failure.

Summary

EGID are rare diseases. However, if a child has unexplained gastrointestinal symptoms, it is essential to seek out a thorough diagnosis. This is even more important in those children with a history of allergic symptoms. If identified early, EGID can be treated by taking an approach that includes dietary modification and possibly pharmacologic intervention.

Dietary intervention will reduce the allergen load on the gastrointestinal tract from food whilst pharmacologic intervention will reduce inflammation and the over-activation of the immune response. Together, they potentially hold promise for your child.

Given the scarcity of research into EoN, EoG and EoC in children, it is of the utmost importance that the scientific community continue to investigate these diseases, to continue to bring hope to the families affected.